Abstract

Vici syndrome is a recessively inherited multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. To investigate the molecular basis of Vici syndrome, we carried out exome and Sanger sequence analysis in a cohort of 18 affected individuals. We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome. EPG5 is the human homolog of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator (ectopic P-granules autophagy protein 5) implicated in the formation of autolysosomes. Further studies showed a severe block in autophagosomal clearance in muscle and fibroblasts from individuals with mutant EPG5, resulting in the accumulation of autophagic cargo in autophagosomes. These findings position Vici syndrome as a paradigm of human multisystem disorders associated with defective autophagy and suggest a fundamental role of the autophagy pathway in the immune system and the anatomical and functional formation of organs such as the brain and heart.

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Acknowledgements

We are grateful to the individuals with Vici syndrome and their families for their participation in this study. We would like to thank our colleagues at the Genomics Facility of the Comprehensive Biomedical Research Centre of Guy's and St Thomas' NHS Foundation Trust for their support. We would also like to thank the physicians D. Creel, R.O. Hoffman and L. Al-Gazali for their input and productive discussions. H.J. was supported by a grant from the Guy's and St Thomas' Charitable Foundation (grant 070404). M.G. and A.L.K. were supported by the Leducq Foundation Transatlantic Network Proteotoxicity (11 CVD 04) and the Medical Research Council of Great Britain (MR/J010456/1). M.G. holds the British Heart Foundation Chair of Molecular Cardiology. H.J. would like to dedicate this work to the memory of Rahul Ghosh, his first patient with Vici syndrome.

Author information

Author notes

    • Thomas Cullup
    •  & Ay Lin Kho

    These authors contributed equally to this work.

    • Mathias Gautel
    •  & Heinz Jungbluth

    These authors jointly directed this work.

Affiliations

  1. DNA Laboratory, Guy's and St Thomas' Serco Pathology, Guy's Hospital, London, UK.

    • Thomas Cullup
    • , Frances Smith
    • , Shu Yau
    •  & Stephen Abbs
  2. Randall Division of Cell and Molecular Biophysics, King's College London, London, UK.

    • Ay Lin Kho
    • , Birgit Brandmeier
    •  & Mathias Gautel
  3. Cardiovascular Division, King's College London British Heart Foundation Centre of Research Excellence, London, UK.

    • Ay Lin Kho
    • , Birgit Brandmeier
    •  & Mathias Gautel
  4. Division of Metabolism, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cure a Carattere Scientifico, Rome, Italy.

    • Carlo Dionisi-Vici
  5. Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cure a Carattere Scientifico, Rome, Italy.

    • Carlo Dionisi-Vici
    •  & Enrico Bertini
  6. Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, UK.

    • Zoe Urry
    •  & Michael A Simpson
  7. Department of Paediatric Neurology, Evelina Children's Hospital, Guy's and St Thomas' National Health Service (NHS) Foundation Trust, London, UK.

    • Verity McClelland
    •  & Heinz Jungbluth
  8. Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

    • Mohammed Al-Owain
  9. Faculty of Medicine, Alfaisal University, Riyadh, Saudi Arabia.

    • Mohammed Al-Owain
  10. Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.

    • Stefan Koelker
    • , Christian Koerner
    •  & Georg F Hoffmann
  11. Department of Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.

    • Frits A Wijburg
    •  & Amber E ten Hoedt
  12. Greenwood Genetic Center, Greenville, South Carolina, USA.

    • R Curtis Rogers
  13. Department of Pediatrics, Clinical Genetics and Metabolism, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, Colorado, USA.

    • David Manchester
  14. Department of Pediatrics, Tokyo Kita Shakai Hoken Hospital, Tokyo, Japan.

    • Rie Miyata
  15. Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

    • Masaharu Hayashi
  16. Section of Medical Genetics, Mater dei Hospital, Msida, Malta.

    • Elizabeth Said
  17. Department of Anatomy & Cell Biology, University of Malta, Msida, Malta.

    • Elizabeth Said
  18. Department of Paediatrics, Mater dei Hospital, Msida, Malta.

    • Doriette Soler
  19. Institute of Human Genetics, Medical University of Graz, Graz, Austria.

    • Peter M Kroisel
    •  & Christian Windpassinger
  20. Division of Pediatric Neurology, University of Utah School of Medicine, Salt Lake City, Utah, USA.

    • Francis M Filloux
  21. Department of Pediatrics, Tawam Hospital, Al-Ain, UAE.

    • Salwa Al-Kaabi
    •  & Jozef Hertecant
  22. Genetics Department, Hospital Vall d'Hebron, Barcelona, Spain.

    • Miguel Del Campo
  23. Department of Clinical Neuropathology, Academic Neuroscience Centre, King's College Hospital, London, UK.

    • Stefan Buk
    •  & Istvan Bodi
  24. Department of Neuropathology, Johannes Gutenberg University Medical Centre, Mainz, Germany.

    • Hans-Hilmar Goebel
  25. Dubowitz Neuromuscular Centre, Institute of Child Health, University College London, London, UK.

    • Caroline A Sewry
  26. Department of Clinical Genetics, Guy's Hospital, London, UK.

    • Shehla Mohammed
    •  & Dragana Josifova
  27. Clinical Neuroscience Division, Institute of Psychiatry, King's College London, London, UK.

    • Heinz Jungbluth

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Contributions

T.C. designed the experiments, performed whole-exome capture, Sanger sequencing, cDNA sequencing and quantitative PCR (qPCR) analysis, analyzed data and wrote the manuscript. A.L.K. and B.B. performed immunostaining, confocal microscopy, cell culture studies and protein blotting. Z.U. performed qPCR analysis. F.S., M.A.S., S.Y. and S.A. prepared and performed whole-exome capture and analyzed the exome sequencing data. C.D.-V., E.B., V.M., M.A.-O., S.K., C.K., G.F.H., F.A.W., A.E.t.H., R.C.R., D.M., R.M., M.H., E.S., D.S., P.M.K., C.W., F.M.F., S.A.-K., J.H. and M.D.C. provided clinical data. S.B., I.B., H.-H.G. and C.A.S. provided and analyzed neuropathological data. S.M. and D.J. provided clinical data and oversaw genetic aspects of the research. M.G. analyzed data obtained from immunostaining, confocal microscopy, cell culture studies and protein blotting and wrote the manuscript. H.J. provided clinical and neuropathological data, analyzed exome and Sanger sequencing data, oversaw all aspects of the research and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Mathias Gautel or Heinz Jungbluth.

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DOI

https://doi.org/10.1038/ng.2497

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